Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it will still take several weeks for it to take effect and improve mood. This time lag has been a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting, even in patients who do not respond well to various other anti-depressants. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex (mPFC) and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine rapid antidepressant actions. However, so far, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. This is very surprising in light of the fact that major depression affects twice as many women as men. Thus, it is especially important to determine whether the same doses of ketamine that are beneficial in male subjects will be efficient in female subjects as well. It is aso important to determine whether the antidepressant effects of ketamine in female rats will implicate the same molecular pathways described in male rats (mTOR in the mPFC and/or eEF2 in the hippocampus) and determine if gonadal hormones, and in particular 17 -estradiol (E2) and its receptors (ER and/or ER), play a role in these effects (in view of the large literature showing interactions between estrogen and the downstream signaling of the NMDAR). Our preliminary data showed that female rats are more sensitive to ketamine antidepressant effects when compared to male rats; a low dose of ketamine (2.5 mg/kg), that is not antidepressant in males, had clear and long-term antidepressant effects in female rats. Excitedly, the antidepressant effects of this low dose of ketamine were completely abolished when female rats were ovariectomized. This effect was completely reversed when E2 benzoate (E2B) -but not progesterone (P4) - was supplemented, suggesting a role for E2 at enhancing the antidepressant effects of ketamine in female rats. Accordingly, in this application we will tes the general hypothesis that gonadal E2 plays a major role in sex differences in the antidepressant effects of ketamine.